ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.137G>T (p.Arg46Leu) (rs772551056)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473045 SCV000554015 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-04-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 46 of the SDHB protein (p.Arg46Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with pheochromocytoma and paraganglioma (PHEO-PGL) syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 412478). Experimental studies have shown that the p.Arg46Leu missense variant severely disrupts protein function in a yeast complementation assay (PMID: 23175444). Two different missense substitution at this codon (p.Arg46Gly, p.Arg46Gln) have been determined to be pathogenic (PMID: 14500403, 15328326, 25972245). This suggests that the arginine residue is critical for SDHB protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000571526 SCV000664561 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-09 criteria provided, single submitter clinical testing The p.R46L variant (also known as c.137G>T), located in coding exon 2 of the SDHB gene, results from a G to T substitution at nucleotide position 137. The arginine at codon 46 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a paraganglioma-pheochromocytoma cohort, and authors characterized this alteration as having severely impaired function based on reduced oxidative growth, SDH activity and respiration, as well as increased mtDNA mutability following oxidative stress (Panizza E et al. Hum. Mol. Genet., 2013 Feb;22:804-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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